This application is a 371 of PCT/JP00/01316 filed Mar. 3, 2000.
This invention relates to new heterocyclic compounds having pharmacological activity, to processes for their production and to a pharmaceutical composition containing the same.
Some imidazole derivatives, which have inhibiting activity to adenosine deaminase (hereinafter described as ADA) are known, for example, by Drug Development Research 28, p253-258 (1993).
This invention relates to novel heterocyclic compounds which have pharmacological activity such as ADA inhibiting activity, to processes for their production, to a pharmaceutical composition containing the same and to a use thereof.
Accordingly, one object of this invention is to provide the novel heterocyclic compounds which have an ADA inhibiting activity.
Another object of this invention is to provide processes for their production of the new heterocyclic compounds.
A further object of this invention is to provide a pharmaceutical composition containing, as active ingredient, the new heterocyclic compounds.
Still further object of this invention is to provide a use of the new heterocyclic compounds for manufacturing a medicament for treating or preventing various diseases.
The new heterocyclic compounds of this invention can be represented by the following general formula (I): 
wherein
B is 
xe2x80x83[wherein R1 is hydrogen or lower alkyl;
R2 is hydrogen or lower alkyl; and
X is hydrogen or hydroxy protective groups], lower alkanoyl or hydroxyimino(lower)alkyl;
A is lower alkylene;
W is heterocyclic or carbocyclic group, each of which may have one or more substituent(s);
Z is heterocyclic group selected from the group consisting of imidazolyl, triazolyl, imidazopyridyl and adenyl, each of which may have one or more substituent(s);
or a salt thereof,
provided that when W is aryl which may have one or more substituent(s), then (i) Z is triazolyl, imidazopyridyl or adenyl, each of which may have one or more substituent(s); (ii) Z is imidazolyl which may have one or more substituent(s) and B is lower alkanoyl or hydroxyimino(lower)alkyl; or (iii) Z is imidazolyl which may have one or more substituent(s) and R1 and R2 are both lower alkyl.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as syn- or anti-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of the formula (I) may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The compounds of the formula (I) and a salt thereof can be in a form of solvate, which is included within the scope of the present invention. The solvate preferably includes a hydrate and an ethanolate.
Also included in the scope of this invention are radiolabelled derivatives of the compounds of formula (I) which are suitable for biological studies.
According to the present invention, the object compound (I) or a salt thereof can be prepared by the processes which are illustrated in the following scheme. 
wherein A, R1, R2, W, X and Z are each as defined above,
R3 is lower alkyl, optionally substituted ar(lower)alkyl, ar(lower)alkylamino, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl, each of which may have one or more substituent(s),
W1 is heterocyclic group or carbocyclic group, each of which has nitro,
W2 is heterocyclic group or carbocyclic group, each of which has amino,
W3 is heterocyclic group or carbocyclic group, each of which has a group of the following formula:
xe2x80x94NHxe2x80x94C(O)xe2x80x94R3 (R3 is as defined above),
X1 is hydroxy protective group,
Z, is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has carboxy,
Z2 is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has guanidinocarbonyl,
Z3 is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has carbamoyl.
R4 is lower alkyl, carbocyclic(lower)alkyl or heterocyclic(lower)alkyl,
W4 is carbocyclic or heterocyclic group, each of which has lower alkylamino, carbocyclic(lower)alkylamino or heterocyclic(lower)alkylamino,
W5 is carbocyclic or heterocyclic group, each of which has a hydroxy protective group,
R5 and R6 are lower alkyl, heterocyclic(lower)alkyl or carbocyclic(lower)alkyl,
R7 is hydrogen or methanesulfonyl,
W6 is heterocyclic or carbocyclic group, each of which has OR5 or OR6 [wherein R5 and R6 are as defined above].
R8 is hydrogen,
R9 is lower alkyl,
R10 is lower alkyl, and
Y is halogen.
The starting compound (II), wherein B is 
can be prepared by the following processes. 
wherein A, R1, R2, W and X1 are each as defined above.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the present invention are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having one to six carbon atom(s), unless otherwise indicated.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkyl moietyxe2x80x9d in the terms xe2x80x9chydroxyimino(lower)alkylxe2x80x9d, xe2x80x9coptionally substituted ar(lower)alkylxe2x80x9d, xe2x80x9car(lower)alkylaminoxe2x80x9d, xe2x80x9cN-containing heterocyclic(lower)alkylxe2x80x9d, xe2x80x9cheterocyclicthio(lower)alkylxe2x80x9d, xe2x80x9cphenyl(lower)alkylaminoxe2x80x9d, xe2x80x9cphenyl(lower)alkylxe2x80x9d, xe2x80x9clower alkylphenyl(lower)alkylxe2x80x9d, xe2x80x9clower alkoxyphenyl(lower)alkylxe2x80x9d, xe2x80x9cbenzimidazolyl(lower)alkylxe2x80x9d, xe2x80x9cpyridyl(lower)alkylxe2x80x9d, xe2x80x9cbenzothiazolylthio(lower)alkylxe2x80x9d, xe2x80x9cindolyl(lower)alkylxe2x80x9d and xe2x80x9clower alkylcarbamoylxe2x80x9d may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like.
Suitable xe2x80x9clower alkylenexe2x80x9d may include straight or branched one having one to eight carbon atom(s), such as methylene, ethylene, propylene, butylene, amylene, hexylene, or the like.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d for W and xe2x80x9cheterocyclic moietyxe2x80x9d in the terms xe2x80x9cheterocyclic(lower)alkylxe2x80x9d heterocyclicthio(lower)alkyl for R3 or R4, etc., may include the one containing at least one heteroatom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or bicyclic heterocyclic group. Preferable heterocyclic group may be N-containing heterocyclic group containing one to four nitrogen atom(s).
Suitable xe2x80x9cN-containing heteromonocyclic groupxe2x80x9d may include the following groups.
(1) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to four nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.;
(2) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to three nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
(3) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, etc.;
(4) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s), for example, morpholinyl, etc.;
(5) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s), for example, thiazolyl, thiadiazolyl, etc.;
(6) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s), for example, thiomorpholinyl, etc.
Suitable xe2x80x9cN-containing heterobicyclic group may include benzimidazolyl, benzothiazolyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, purinyl, adenyl, quinolyl, isoquinolyl, etc.
Suitable non N-containing heterocyclic group may include the following groups.
(1) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
(2) unsaturated 3 to 8-membered (more preferably 5 or 6-memberd) heteromonocyclic group containing an oxygen atom, for example, furyl, pyranyl, etc.;
(3) saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s), for example, oxiranyl, oxolanyl, dioxolanyl, tetrahydrofuranyl, etc.;
(4) unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
(5) unsaturated condensed heterocyclic group containing 1 to 4 oxygen atom(s), for example, methylenedioxyphenyl, benzodioxanyl, etc.;
(6) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
(7) unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl; and the like.
Suitable xe2x80x9ccarbocyclic groupxe2x80x9d may be the one having three to ten carbon atoms, saturated or unsaturated such as cyclo(lower)alkyl or aryl, more preferably aryl, each of which may have one or more substituent(s).
Suitable xe2x80x9csubstituentxe2x80x9d in the terms xe2x80x9cheterocyclic or carbocyclic groupxe2x80x9d for W, xe2x80x9cheterocyclic group selected from the group consisting of imidazolyl, imidazopyridyl, triazolyl or adenylxe2x80x9d for Z, and xe2x80x9clower alkyl, optionally substituted ar(lower)alkyl, ar(lower)alkylamino or heterocyclic(lower)alkyl, each of which may have one or more substituent(s)xe2x80x9d for R3 may include lower alkyl; hydroxy; lower alkoxy; amino; nitro; cyano; halogen; oxo; carboxy; esterified carboxy; carbamoyl, N-substituted carbamoyl; guanidinocarbonyl; aminotriazolyl; substituted or unsubstituted heterocyclic group; a group of the following formula; xe2x80x94NHC(O)xe2x80x94R3 (wherein R3 is as defined above); acyl; or the like.
Suitable xe2x80x9csubstituentxe2x80x9d for xe2x80x9cN-substituted carbamoylxe2x80x9d is lower alkyl such as the one mentioned above.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxy moietyxe2x80x9d in the terms of xe2x80x9coptionally substituted (lower)alkoxyxe2x80x9d, xe2x80x9cphenyl(lower)alkoxyxe2x80x9d, xe2x80x9chalophenyl(lower)alkoxyxe2x80x9d, xe2x80x9cindolyl(lower)alkoxyxe2x80x9d and xe2x80x9clower alkoxycarbonylxe2x80x9d may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, and the like.
Suitable xe2x80x9clower alkanoylxe2x80x9d may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.
Suitable xe2x80x9chalogenxe2x80x9d and xe2x80x9chalogen moietyxe2x80x9d in the term xe2x80x9chalophenyl(lower)alkoxyxe2x80x9d may be fluoro, chloro, bromo, or iodo.
Suitable xe2x80x9cesterified carboxyxe2x80x9d may be substituted or unsubstituted lower alkoxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc., substituted or unsubstituted aryloxycarbonyl, for example, phenoxycarbonyl, 4-nitrophenoxycarbonyl, and the like.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
Suitable xe2x80x9carylxe2x80x9d and xe2x80x9caryl moietyxe2x80x9d in the terms xe2x80x9coptionally substituted ar(lower)alkylxe2x80x9d, xe2x80x9car(lower)alkylaminoxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d may be phenyl, naphtyl, tolyl, xylyl, and the like.
Suitable xe2x80x9chydroxy protective groupxe2x80x9d may include common protective group and the like.
Suitable xe2x80x9ccommon protective groupxe2x80x9d may include acyl, mono(or di or tri)phenyl(lower)alkyl which may have one or more substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
Suitable xe2x80x9cacylxe2x80x9d may include aliphatic acyl group and acyl group containing an aromatic ring or heterocyclic ring.
And, suitable examples of the said acyl may be lower alkanoyl, lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.).
Preferred embodiments of the object compounds (I) are represented by the following formula:
A compound of the formula [I]: 
wherein
B is 
xe2x80x83[wherein R1 is hydrogen;
R2 is hydrogen or lower alkyl; and
X is hydrogen],
A is ethylene;
W is indolyl, benzothiazolyl,indazolyl, phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of cyano, hydroxy, halogen,oxo, lower alkoxy, pheny(lower)alkoxy, halophenyl(lower)alkoxy, indolyl(lower)alkoxy which may have lower alkyl, lower alkyl, phenyl(lower)alkylamino, amino, nitro and xe2x80x94NHxe2x80x94C(O)xe2x80x94R3 [wherein R3 is lower alkyl, phenyl(lower)alkyl, lower alkylphenyl(lower)alkyl, lower alkoxyphenyl(lower)alkyl, phenyl(lower)alkylamino, phenyl, benzimidazolyl(lower)alkyl which may have lower alkyl, pyridyl(lower)alkyl, benzothiazolylthio(lower)alkyl or indolyl(lower)alkyl which may have one or two oxo]; and
Z is imidazolyl, triazolyl or imidazopyridyl, each of which may have one substituent selected from the group consisting of carbamoyl, lower alkylcarbamoyl, (lower)alkoxycarbonyl and guanidinocarbonyl.
or a salt thereof.
More preferred embodiments of the object compound [I] are represented by the following formula:
A compound of the formula [I]: 
wherein
B is 
xe2x80x83[wherein R1 is hydrogen;
R2 is hydrogen or lower alkyl; and
X is hydrogen],
A is ethylene;
W is indolyl, benzothiazolyl,indazolyl, phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of cyano, hydroxy, halogen,oxo, lower alkoxy, pheny(lower)alkoxy, halophenyl(lower)alkoxy, indolyl(lower)alkoxy which may have lower alkyl, lower alkyl, phenyl(lower)alkylamino, amino, nitro and xe2x80x94NHxe2x80x94C(O)xe2x80x94R3 [wherein R3 is lower alkyl, phenyl(lower)alkyl, (lower)alkylphenyl(lower)alkyl, (lower)alkoxyphenyl(lower)alkyl, phenyl(lower)alkylamino, phenyl, benzimidazolyl(lower)alkyl which may have lower alkyl, pyridyl(lower)alkyl, benzothiazolylthio(lower)alkyl or indolyl(lower)alkyl which may have one or two oxo]; and
Z is imidazolyl which may have carbamoyl or guanidinocarbonyl; triazolyl which may have carbamoyl, (lower)alkylcarbonyl or lower alkoxycarbonyl; or imidazopyridyl,
or a salt thereof.
Further more preferred embodiments of the object compound [I] are represented by the following formula:
A compound of the formula [I]: 
wherein
B is 
xe2x80x83[wherein R1 is hydrogen;
R2 is hydrogen or lower alkyl; and
X is hydrogen],
A is ethylene;
W is indolyl which may have one or two substituent(s) selected from the group consisting of cyano, hydroxy, halogen, oxo, lower alkoxy, pheny(lower)alkoxy, halophenyl(lower)alkoxy, indolyl(lower)alkoxy which may have lower alkyl, lower alkyl, phenyl(lower)alkylamino, amino, nitro and xe2x80x94NHxe2x80x94C(O)xe2x80x94R3 [wherein R3 is lower alkyl, phenyl(lower)alkyl, (lower)alkylphenyl(lower)alkyl, (lower)alkoxyphenyl(lower)alkyl, phenyl(lower)alkylamino, phenyl, benzimidazolyl(lower)alkyl which may have lower alkyl, pyridyl(lower)alkyl, benzothiazolylthio(lower)alkyl or indolyl(lower)alkyl which may have one or two oxo]; benzothiazolyl which may have oxo; indazolyl; phenyl which may have one or two halogen(s); or naphthyl; and
Z is imidazolyl which may have carbamoyl or guanidinocarbonyl; triazolyl which may have carbamoyl, (lower)alkylcarbonyl or lower alkoxycarbonyl; or imidazopyridyl,
or a salt thereof.